An important CFIDS marker has renewed the interests of scientists who pursue a mitochondrial connection with this disease.

The Australian research team of Dr. Allan Evans and Dr. Stephanie Reuter have published a journal article and have been issued a patent on acylcarnitine markers found in CFIDS/ME patients [1,2]. This article has broadened the previous research findings initially discovered by Japanese researchers, Kuratsune et. al., and first reported upon at the 1992 Albany, N.Y. conference almost twenty years ago [3]. Since that time period, Kuratsune has published numerous additional journal articles in addition to being issued patents as well [4-11].

Since scientists first highlighted abnormalites relating to acylcarnitine metabolism in CFIDS/ME patients, you might ask why this is so important to the clinical picture of this disease? Well, largely due to the fact that carnitine plays a critical role in mitochondrial energy production. Furthermore, since CFIDS/ME patients have been identified as having a substantially reduced quality of life, could acylcarnitine then be an important factor in the pathophysiology of this disease [12]? The NCF certainly believes this is the case and, fortunately for us, our own research efforts illuminate this as well.

In general, alterations to carnitine homeostasis can have a detrimental impact on human health. Carnitine deficiency has been associated with cardiomyopathy, encephalopathy, muscle weakness and heart failure. Technically speaking, the actual biological role of carnitine is to transport fatty acids across the inner mitochondrial membrane for fatty acid oxidation via the reversible binding of acyl groups from CoenzymeA. Carnitine also serves in the transport of short and medium acyl groups from the peroxisome to the mitochondria as well as to remove unwanted acyl groups from the body.

Drs. Evans and Reuter have focused their primary efforts on examining the details and identification of various individual acylcarnitines as opposed to total acylcarnitines that Kuratsune looked at. Evans and Reuter analyzed thirty-five individual acylcarnitine levels from forty-four patients and forty-nine age and sex-matched controls using tandem mass spectrometry. Patients were recruited from the Chronic Fatigue Syndrome Society of South Australia.

This study had found that in most patients, the acylcarnitine levels differed by approximately 20% between patients and controls with patients exhibiting lower acylcarnitine levels overall. However, certain specific acylcarnitines were 30 - 40% lower in patients with CFIDS/ME than in healthy controls. Statistical analysis identified significant reductions (p<0.0001) in dodecanedioyl-L-carnitine, oleyl-L-carnitine and linoleyl-L-carnitine levels present in patient samples. This study had also demonstrated significant relationships between the severity of fatigue and acylcarnitine levels. Lower levels of oleyl-L-carnitine and linoleyl-L-carnitine in patients were associated with greater fatigue severity. Evans and Reuter's latest study confirms the presence of a long-chain acylcarnitine deficiency in patients with CFIDS/ME.

At this point you may be asking "Are there any potential therapies for this?" Yes,several have been suggested. In a previous study, Kuratsune had shown that patients with CFIDS/ME improved with two grams of acetyl-L-carnitine taken twice per day (for a total of four grams per day) and that this improvement was associated with a concurrent increase in plasma acylcarnitine levels [6].

In this study however, Evans and Reuter suggest that the deficiency in long-chain acylcarnitine in patients may be reflective of either (i) an increase in the activity of carnitine-acylcarnitine translocase (CACT) or (ii) a reduction in carnitine palmitoyltransferase-I activity (CPT-I). These authors conclude that it is likely that there is a reduction in CPT-I and that the applicable therapy for this would be via combinational administration of L-carnitine along with omega-3 fatty acids.

Regarding alterations to CACT activity, Evans and Reuter concluded that "an increase in CACT activity would result in enhanced long-chain acylcarnitine transfer across the inner mitochondrial membrane and hence an increase in substrate availability for muscle beta-oxidation, a scenario that is improbable given the symptomology of chronic fatigue syndrome." Here is where the NCF differs from these authors as we have learned the hard way that nothing is "improbable" in science!

Let me explain. First, Dr. Yoshitsugi Hokama has been able to show that modifications to cardiolipin as well as anticardiolipin antibodies are present in CFIDS/ME patients and that this is related to patient sera reactivity to the monoclonal antibody for ciguatera toxin (Mab-CTX) identified previously in this patient population [13-15]. Both cardiolipin and anticardiolipin antibodies impact the mitochondrial inner and outer membranes [16]. CACT is associated with the inner mitochondrial membrane and it acts to modify the import of acylcarnitines into the mitochondria [17]. Thus, it is probable that direct modifications to cardiolipin, or indirectly via anticardiolipin antibodies, could impact the functionality of CACT to thereby alter acylcarnitine levels. This is likely since cardiolipin is required for CACT activity, something overlooked by Evans and Reuter [18].

Secondly, the NCF has made countless observations on this journey because of patients sharing their CFIDS/ME stories. Several years ago, the NCF sent out a survey to women with this disease who went on to develop breast cancer. While chatting with patients, several women alluded to the fact that their CFIDS/ME disease symptoms resolved when on adriamycin, also known as doxorubicin, taken for their breast cancer treatment. Well adriamycin inhibits CACT activity [18]. Not only may this be a "therapeutic hint" but it may also help to explain anecdotally why there was an overall improvement in CFIDS/ME symptoms. Something that must be remembered is that CFIDS/ME patient mitochondria aren't necessarily intact nor do they function at 100%. Certainly, we are aware of this fact due to previous mitochondrial reports [19-21]. In fact, intact or non-intact mitochondria directly affect the functionality of the CACT system and this possibility has been overlooked by Evans and Reuter [22].

Thirdly, since Kuratsune found acetyl-L-carnitine to improve CFIDS/ME patient symptoms, the NCF asked if acetyl-L-carnitine affects CACT. In aged rats, acetyl-L-carnitine not only modulates CACT levels but it also modifies cardiolipin as well [23]. This may provide additional therapeutic hints regarding its use in patients.

Lastly, since the NCF peruses a great deal of information, we came across a patent that we believe is most applicable here as it provides additional therapeutic hope to patients [24]. This patent was issued to Dr. Paul Jenkins, from England, and pertains to the use of trimetazidine, also known as Vastarel MR modified release formulation, for use in CFIDS/ME patients as a way to reduce mitochondrial fatty acid oxidation and beta-oxidation. Jenkins also mentions the use of ranolazine, also known as Ranexa, for this as well. In patient application, Jenkins utilized 35mg of oral trimetazidine twice per day for the relief of symptoms related to CFIDS/ME. As mentioned above, fatty acid and/or beta-oxidation levels may be due to alterations in CACT as discussed by Evans and Reuter. In a brief search before this article went to press, the NCF was able to find that fatty acid oxidation inhibitors have been employed by patients with heart failure and one of the drugs utilized was trimetazidine [25].

As Medical Director, I frequently receive phone calls regarding "the availability for any hopeful therapies for use in this horrible disease." I believe that the open discussion of this science and its implications will have important and practical ramifications for CFIDS/ME patients worldwide.

Disclaimer: This column is NOT intended to act as medical advice in any way, shape or form! The National CFIDS Foundation assumes no responsibilities for any action or treatment undertaken by readers. For medical advice, please consult with your own personal healthcare providers.